Stable pharmaceutical compositions without a stabilizer

ABSTRACT

Stabilized controlled release pharmaceutical preparations are disclosed in which active ingredient degradation is prevented without the use of a stabilizer. The active ingredient is sealed away from excipients that can adversely affect stability by sealing the excipients rather than the active ingredient. The preparations are substantially unaffected by exposure to storage conditions of elevated temperature and/or elevated relative humidity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 10/301,474 filed Nov. 21, 2002 now U.S. Pat. No.6,893,660.

FIELD OF THE INVENTION

The present invention relates to novel, stable oral controlled-releasedosage formulations without the need for acid stabilizers. Morespecifically, the present invention relates to highly stable solid oraldosage formulations in the form of a tablet or pellets that maintain atleast 90% of initial drug or other active ingredients potency after oneyear.

BACKGROUND OF THE INVENTION

Stability is an important aspect of all forms of controlled releasedosage forms and other formulations for active ingredients. Stabilitystudy requirements are covered in the United States Pharmacopia 24^(th)Edition (USP XXIV), in the Good Manufacturing Practices (GMP) as well asin FDA Guidelines. The ingredients used in controlled release dosageforms often present special problems with regard to their physicalstability during storage. Strategies used in the prior art to stabilizecontrolled release formulations include: insuring the individualingredients are in a stable form prior to their incorporation into theproduct; retarding the instability by adding additional ingredients;inducing the individual ingredients to reach a stable state before theproduct is completed; changing the porosity and/or hydration level of apolymeric film to adjust the moisture content of the product; and properpackaging of the product.

In some instances, active ingredients of solid controlled releaseformulation degrade by hydrolysis. For example, hydrolysis of bupropionhydrochloride is encouraged in environments where the pH is above 4, aswell as in the presence of (hydrophilic) excipients. The prior art showsthat hydrolysis of certain active ingredients can be retarded in anacidic environment. Accordingly, acidified additives or formulationshave been used to retard degradation.

Examples of prior art formulations of the drug bupropion hydrochloridedemonstrate the use of acidic stabilizing ingredient to preventdegradation of the active ingredient. Bupropion hydrochloride is anaminoketone-derivative designated as(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl) amino]-1-propanonehydrochloride and described in U.S. Pat. Nos. 5,358,970; 5,427,798;5,731,000, 5,763,493; Re. 33,994; 3,819,706 and U.S. Pat. No. 3,885,046.It is marketed as an antidepressant and as an aid to smoking cessation.The drug is chemically unrelated to tricyclic, tetracyclic or selectiveserotonin-reuptake inhibitors. Noradrenergic pathways and/ordopaminergic effects appear to be the primary mechanism forantidepressant and smoking cessation actions. The dosing regimen forsustained-release bupropion is once or twice daily.

The stability of bupropion hydrochloride and other active ingredientsmay be affected by factors including formulation and storage conditions.Heat lability of bupropion hydrochloride formulations is known. Althoughbupropion hydrochloride is stable in bulk and in most simple blends, thedrug is unstable in complex mixtures such as granulations or tablets.

Stability studies of mixtures with lubricants show that bupropion isstable in the presence of talc but stability is poor in the presence ofmagnesium stearate or stearic acid. A lubricant, such as, magnesiumstearate is often added to prevent picking and sticking on a high-speedrotary press. Bupropion formulations without stabilizers lose more than50% of active ingredient potency at six weeks of accelerated conditions.

Labeling of conventional tablets or extended-release tablets ofbupropion hydrochloride indicates storage at a temperature of 15-25° C.and protection from light and moisture. Extended release tablets ofbupropion should be stored in tight, light-resistant containers at atemperature of 20-25° C. (USP Pharmacopeial Forum, Vol. 26(4):July-August 2000).

The prior art describes the use of stabilizers to prevent degradation ofthe active ingredient. For example, the patents summarized below teachthe addition of an organic or inorganic acid as a separate stabilizingingredient for formulations of bupropion hydrochloride.

Sustained release tablet forms of bupropion are described in U.S. Pat.No. 5,427,798, comprising a sustained release tablet where controlledrelease is achieved by combining bupropion particles withmicrocrystalline cellulose and hydrogel-forming high molecular weight,high viscosity grades of hydroxypropyl methylcellulose. Stabilization ofthis formulation is taught by addition of cysteine hydrochloride orglycine hydrochloride.

Stabilization by acidification of the environment in which degradationoccurs in pharmaceutical compositions containing bupropion is disclosedin U.S. Pat. No. 5,968,553. In this patent, the stabilizer is aninorganic acid having an aqueous solution pH of about 0.5 to 4.0 at aconcentration of about 0.31% w/w. The inorganic acids are selected fromthe group consisting of hydrochloric acid, phosphoric acid, nitric acid,and sulfuric acid. The stabilizer constitutes from about 0.01% to about5% of the amount of bupropion hydrochloride in the composition.

Solid bupropion formulations containing acidic stabilizers are alsodisclosed in U.S. Pat. No. 5,358,970 where the stabilizer has an aqueouspH of about 0.9 to 4.0 at an aqueous solution concentration of about 6%w/w and are solid or liquid at 30° C. Stabilizers used are selected fromthe group consisting of L-cysteine hydrochloride, glycine hydrochloride,ascorbic acid, malic acid, sodium metabisulfite, isoascorbic acid,citric acid, tartaric acid, L-cysteine dihydrochloride or theircombinations.

Stabilization of the commercially available Wellbutrin® SR is achievedby acidification with L-cysteine hydrochloride.

Although the prior art teaches incorporating acidification additives toreduce the hydrolytic degradation of active ingredients, it is lessdesirable because: 1) it may not be suitable for pharmaceuticalcompositions with basic excipients and 2) it represents additionalingredients in the formulation. The need exists for a stable controlledrelease bupropion formulation that does not require a stabilizer andwhich may be used with basic excipients. Such delayed delivery dosageformulations have a practical application, and represent a valuablecontribution to the medical arts. The present invention provides suchcompositions, and offers efficient and cost effective methods ofpreparation.

SUMMARY OF THE INVENTION

The present invention meets the unfulfilled needs of the pharmaceuticalindustry by providing a stable oral dosage formulation that overcomesthe problems of the prior art. The present invention may also haveapplication to other solid delivery forms of active ingredients, such asalgicides, antioxidants, air purifiers, biocides, bactericides,catalysts, chemical reactants, disinfectants, fungicides, fermentationagents, fertility inhibitors, fertility promoters, germicides,herbicides, insecticides, microorganism attenuators, pesticides, plantgrowth promoters, plant growth inhibitors, preservatives, rodenticides,sterilization agents, sex sterilants, and the like.

Accordingly, it is an object of this invention to provide a novel anduseful sustained-release formulation that is free of any organic orinorganic acid stabilizing additive component. This represents anunexpected improvement in the art and substantially overcomes thedisadvantages known to the prior art.

It is an object of the present invention to provide a formulation forsolid delivery forms of other active ingredients.

It is also an object of the present invention to provide both a methodof stabilizing bupropion hydrochloride to slow the degradation thereofand provide products that can be stored for long periods of time at roomtemperature, i.e., under humidity and temperature conditions usuallyencountered in pharmacies and medicine cabinets. It is a further objectto provide solid oral dosage forms where the amount of active drug willbe prevented from being reduced to less than about 90% of its labeledstrength, and more preferably not less than about 95% of the labeledstrength after one year of storage under the aforementioned usuallyencountered conditions.

It is also an object of the invention to provide an acid free,sustained-release bupropion dosage system that is therapeutically orbiologically equivalent to sustained-release bupropion formulations thatcontain an organic or inorganic acid.

It is an object of the invention to produce a stable formulation ofbupropion hydrochloride suitable for once daily administration, in theform of a blend of beads or pellets as a tablet or capsule dosage formthat overcomes the need to add stabilizers.

Other objects, features and advantages of the invention are not taughtin the prior art but will be more apparent to those versed in the artfrom the following specification, taken in conjunction with theaccompanying claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides sustained-release formulations that can providean alternative to the prior art formulations. The prior art formulationstypically require the presence of a stabilizer, such as an organic orinorganic acid. An embodiment of the subject invention provides for astable bupropion hydrochloride formulation for once or twice dailydosing without the need for adding the acid or other stabilizingcomponent.

Unlike the prior art, the subject invention favorably influencesstability by physically sealing the excipients rather than chemicallyadjusting pH. In this novel formulation, stability is achieved, even inhigher pH environments, by sealing the excipients rather than sealingthe active drug, as has been previously done. This protective coatingthereby prevents the absorption of moisture by the excipients duringstorage. Thus, the invention can be applied to any drug or other activecomponent that will undergo hydrolytic decomposition in the presence ofmoisture and/or other moisture triggered decomposition reactions orother destabilization mechanisms. In one embodiment of the presentinvention the composition of the sealed excipient and active ingredientretains at least 85% of the undegraded active ingredient after storagefor 3 months at about 40° C. and about 75% relative humidity.

Stabilizer, as the term is used herein, refers to compounds capable ofchemically inhibiting or preventing degradation of bupropionhydrochloride. Stabilizers in prior art formulations were added toformulations of bupropion hydrochloride to improve chemical and physicalstability. According to previous bupropion formulations containingstabilizers, tablets should retain about 80-90% or more of activeingredient at the end of one year in the presence of stabilizers.

The stability of bupropion hydrochloride formulated according to thepresent invention, without stabilizers, was tested in accordance withand exceeded current pharmaceutical industry standards for storage(i.e., four to twelve weeks at about 40° C. and about 75% relativehumidity). Formulations of the present invention stored under theseconditions retain at least about 90% of the bupropion hydrochloridepresent in the composition at the time of storage. In many instances,formulations of the present invention retain more than about 95% oftheir original potency, and more preferably retain at least about 98% ofbupropion hydrochloride present in the composition at the time ofstorage. Standard procedures such as HPLC or UV spectroscopic methodsmay be used to determine the amount of active ingredient remaining afterstorage. Shelf life assay limits of 90 to 110 percent of the labeledstrength tablet are applied. The design of the stability studies was incompliance with the general requirements suggested by the FDA stabilityguidelines.

The total amount of inactive ingredients in the formulations ispreferably 30% or more of the weight of the bupropion.

Pharmaceutical compositions of the present invention generally containfrom about 50 to about 300 mg of bupropion hydrochloride as the activeingredient. More preferably, compositions of the invention contain about100 mg to about 200 of active ingredient and may be in the form oftablets, caplets or capsules.

Pharmaceutical compositions of the present invention as in Example 1below, may contain combinations of low and high molecular weightosmopolymers. Osmopolymers are swellable, hydrophilic polymers thatinteract with water and aqueous biological fluids causing theosmopolymer to swell or expand and retain water in the polymerstructure. One preferred group of osmopolymers are the polyethyleneoxides. The preferred polyethylene oxides are those with highermolecular weight, i.e., 2×10⁶ and higher, that provide delayed drugrelease via the hydrophilic polymer matrix. The drug release proceeds asa controlled diffusion, dependent on the molecular weight (hereinafter“MW”) of the polyethylene oxide (PEO); the higher the MW, the slower therate of drug released. A preferred PEO is Poly-ox WSR Coagulant (MW5,000,000, viscosity 5,500-7,500 mPa·s at 25° C.).

The addition of an osmagent may enhance the regulation of the rate ofdiffusion through the membrane and thus enhance regulation of the rateof drug release. Preferred water-soluble resins for use as osmagents arethose with MWs less than 0.6×10⁶. Most preferred is Poly-ox WSR N-80 (MW200,000) (viscosity of 65 to 115 mPa·s at 25° C.). When the drug isformulated by combining the higher MW polyethylene oxides (viscosity of5000 to 20,00 mPa·s at 25° C.) with low MW polyethylene oxides(viscosity of 50 to 200 mPa·s at 25° C.), the release is controlled bythe swelling of the polymer as well as by polymer erosion, therebyproducing a substantially constant rate of delivery over a 24 hourperiod. A preferred concentration of the high MW to low MW polyethyleneoxides for bupropion was determined to be a mixture of about 1:1.24(wt./wt.) although other ratios are within the contemplated scope of thepresent invention.

The present invention discloses stabilization of the controlled releasedosage form without the need for chemical stabilizers by sealing the lowand high molecular weight polyethylene oxides with a water-solublepolymer, thereby physically separating them away from the bupropion. Anyof the known film forming water-soluble polymers may be used in thisregard. For example, water-soluble polymers such ashydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC)may be used as seal coats for the polyethylene oxides in thisapplication. Generally, the HPC and HPMC useful as seal coats in thepractice of the present invention have average molecular weights of80,000 to 1,150,000, and 12,600 to 104,000, respectively. Preferred ishydroxypropylcellulose as in Examples 1.

Also, an effective amount of any generally accepted pharmaceuticallubricant may be added to compress the tablet cores of Example 1. Tabletlubricants are preferably selected from the group consisting of glycerylmonostearates, magnesium stearate, calcium stearate or stearic acid.Most preferably, magnesium stearate is present as a lubricant to preventthe tablets from sticking during processing on a high-speed rotarypress. Magnesium stearate is added to the granulation to assistcompression. In the preferred embodiment in Example 1 below, themagnesium stearate is used in an amount of less than about 1% by weightof the tablet, although other amounts known to those skilled in the artmay be employed.

A glidant or anti-caking agent also may be employed in the practice ofthe present invention. Suitably, these may be chosen from any known suchagents, such as, for example, colloidal silicon dioxide or talc. InExample 1 below, colloidal silicon dioxide is the preferred glidant.

Lactose may also be added as a tabletting filler, or diluent, which canaid in the processing and tableting. The use of lactose can be seen inExample 1. Preferably, anhydrous lactose may be used as a diluent. In apreferred embodiment, the optimal amount of lactose is found to be fromabout 25% to about 40% by weight of the formulation. Other suchexcipients known to those skilled in the art, such as sucrose, dextrose,lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, andmixtures thereof also may be used.

The following examples illustrate the present invention and are notintended to limit the scope of the present invention.

EXAMPLE 1

The formulation contained the following ingredients in the followingamounts:

Weight(mg)/Tablet % (Wt.) Bupropion hydrochloride 150.0 49.83Polyethylene Oxide (M.W. 200,000) 59.4 19.93 Polyethylene oxide (M.W.5,000,000) 47.7 15.95 Hydroxypropylcellulose 12.8 4.32 Lactose Anhydrous27.7 9.30 Colloidal Silicon Dioxide 1.5 0.50 Magnesium stearate 0.9 0.30TOTAL 300.0 100.13

In a GPGC-5 Glatt fluid-bed processor 2.477 kg of polyethylene oxide(M.W. 200,000) and 1.99 kg of polyethylene oxide (M.W. 5,000,000) wereloaded. A solution of hydroxypropyl cellulose (0.532 kg) in acetone andisopropyl alcohol (2:1) was sprayed on the powders using the followingsettings:

Inlet air temperature 26-28° C. Air volume 450-480 m³/h Outlet airregulation flap 50 Shaker interval 2 seconds every 22 seconds Pump rate30-70 mL/min Atomization pressure 2.5 bar

After all the solution was sprayed, the granules were dried in thefluid-bed processor until the loss on drying (LOD) reached below 1%. Thegranules were unloaded from the fluid-bed processor and passed through a20 mesh screen.

The bupropion hydrochloride, lactose, colloidal silicon dioxide wereweighed out and sifted through a 30 mesh screen. The sifted ingredientswere then blended with polyethylene oxide granules for 15 minutes. Aftermixing with magnesium stearate (sifted through a 30 mesh screen) for 5minutes, the blend was compressed into tablets using 11/32″ round,standard concave tooling.

Product stability data were obtained for this formulation stored for 5months under accelerated conditions (40° C. and 75% relative humidity).The tablets retained 99.5% potency after 5 months of storage at 40° C.and 75% relative humidity.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof that donot depart from the spirit and scope of the invention.

The above-referenced patents and publications are hereby incorporated byreference.

The invention claimed is:
 1. A method for stabilizing solid bupropionpharmaceutical preparations by preventing direct contact between: (i)bupropion or a pharmaceutically acceptable salt thereof; and (ii) one ormore excipients that have a negative effect on stability of saidbupropion or pharmaceutically acceptable salt thereof; said methodcomprising: (a) sealing said one or more excipients that have a negativeeffect on stability of said bupropion or pharmaceutically acceptablesalt thereof with a protective coating consisting ofhydroxypropylcellulose, hydroxypropyl methylcellulose and mixturesthereof to prevent the absorption of moisture by said one or moreexcipients that have a negative effect on stability of said bupropion orpharmaceutically acceptable salt thereof to form a sealed excipientcomponent; (b) drying said sealed excipient component until the loss ondrying (LOD) is less than 1%; and (c) dry blending said sealed excipientcomponent with bupropion or a pharmaceutically acceptable salt thereofto form a stable solid preparation without an additional stabilizer;wherein said stable solid preparation retains at least 85% w/w ofundegraded bupropion or pharmaceutically acceptable salt thereof afterstorage for 3 months at about 40° C. and about 75% relative humidity. 2.The method of claim 1, wherein said pharmaceutically acceptable salt ofbupropion is bupropion hydrochloride.
 3. The method of claim 1, whereinsaid preparation is in the form of a tablet.
 4. The method of claim 1,wherein said preparation is in the form of a capsule.
 5. The method ofclaim 1, wherein the protective coating is hydroxypropyl cellulose. 6.The method of claim 1, wherein the protective coating is hydroxypropylmethylcellulose.
 7. The method according to claim 1, wherein the amountof bupropion or pharmaceutically acceptable salt thereof ranges fromabout 75 to about 300 mg.
 8. The method according to claim 1, whereinthe amount of bupropion or pharmaceutically acceptable salt thereof is150 mg.
 9. The method according to claim 1, wherein the amount ofprotective coating comprises 2% to 20% of the total weight of the soliddosage delivery form.
 10. The method according to claim 1, wherein theamount of protective coating comprises less than 15% of the total weightof the solid dosage delivery form.
 11. The method according to claim 1wherein the one or more excipients that have a negative effect onstability of said bupropion or pharmaceutically acceptable salt thereofsealed in step (a) is an osmopolymer.
 12. A stable sustained releasebupropion dosage form prepared according to the method of claim
 1. 13. Amethod for preparing a stable sustained release bupropion solid dosageform comprising: (a) preparing a sealing coating solution consisting ofwater soluble polymers and an organic solvent; (b) coating anosmopolymer with the sealing coating solution; and (c) dry blending thecoated osmopolymer with bupropion or a pharmaceutically acceptable saltthereof and at least one pharmaceutically acceptable excipient to form astable composition comprising bupropion or pharmaceutically acceptablesalt thereof that is free of any organic or inorganic acid stabilizingadditive; wherein the stable composition retains at least 85% w/w ofundegraded bupropion after storage for 3 months at about 40° C. andabout 75% relative humidity.
 14. The method according to claim 13further comprising the step of compressing the stable composition into atablet.
 15. The method according to claim 13 further comprising the stepof placing the stable composition into a capsule.
 16. The methodaccording to claim 13 further comprising the step of drying the coatedosmopolymer until the loss on drying (LOD) is less than 1%.
 17. Themethod according to claim 13 wherein said pharmaceutically acceptablesalt of bupropion is bupropion hydrochloride.
 18. A stable sustainedrelease bupropion dosage form prepared according to the method of claim13.